Acute liver failure (ALF) affects over two thousand Americans per year and results in approximately four hundred liver transplants annually. Defined as the abrupt loss of hepatocellular function in patients with previously normal liver function, the most common etiologies are acetaminophen overexposure and acute viral hepatitis. See Stravitz et al., 6 NAT REV. GASTROENTEROL. HEPATOL. 542-53 (2009). In the most severe cases, patients manifest a rapidly developing coagulopathy, and encephalopathy that progresses to cerebral herniation and death without prompt liver transplantation. See Lee et al., 47 HEPATOLOGY 1401-15 (2008). Fewer than half of patients with ALF will spontaneously recover with supportive care alone, yet at present, no pharmacologic or adjunct therapies have been shown to be of benefit in this clinical scenario. For these critically ill patients, liver transplantation frequently represents the only option for survival; however, this limited resource may be inaccessible at the time at which it is emergently needed. Furthermore, the decision to proceed to transplantation is not always straightforward, because some patients will spontaneously recover, but the ability to predict recovery is markedly limited. Under aggressive utilization of liver transplantation can result in devastating outcomes in potentially salvageable patients, while overly aggressive utilization of transplantation both commits patients who might have spontaneously recovered to a lifetime of immunosuppression, and also unnecessarily utilizes precious grafts that could be allocated to others in need. New therapies, particularly those that can promote spontaneous recovery and lessen the need for liver transplantation, are badly needed.